Alleviate Disease Progression Research Articles

Inhibition of MEK signaling prevents SARS-CoV2-induced lung damage and improves the survival of infected mice.

Coronavirus disease 2019 (COVID‐19) is the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Over 500 million confirmed cases of COVID‐19 have been recorded, with six million deaths. Thus, reducing the COVID‐19‐related medical burden is an unmet need. Despite a vaccine that is successful in preventing COVID‐19‐caused death, effective medication to relieve COVID‐19‐associated symptoms and alleviate disease progression is still in high demand. In particular, one in three COVID‐19 patients have signs of long COVID syndrome and are termed, long haulers. At present, there are no effective ways to treat long haulers. In this study, we determine the effectiveness of inhibiting mitogen‐activated protein kinase (MEK) signaling in preventing SARS‐CoV‐2‐induced lung damage in mice. We showed that phosphorylation of extracellular signal‐regulated kinase, a marker for MEK activation, is high in SARS‐CoV‐2‐infected lung tissues of mice and humans. We also showed that selumetinib, a specific inhibitor of the upstream MEK kinases, reduces cell proliferation, reduces lung damage following SARS‐CoV‐2 infection, and prolongs the survival of the infected mice. Selumetinib has been approved by the US Food and Drug Administration to treat cancer. Further analysis indicates that amphiregulin, an essential upstream molecule, was upregulated following SARS‐CoV‐2 infection. Our data suggest that MEK signaling activation represents a target for therapeutic intervention strategies against SARS‐CoV‐2‐induced lung damage and that selumetinib may be repurposed to treat COVID‐19.

Dysbiosis: Gut feeling

A healthy host-microbiome relationship, crucial for intestinal homeostasis, is established early in postnatal life. Imbalance in the neonatal microbiome may lead to the development of chronic pathological conditions later in life. Dysbiosis of the gut microbiota is increasingly being linked to the etiology of both intestinal and systemic illnesses such as irritable bowel disease (IBD), cardiovascular diseases and diabetes, as well as kidney and neurological disorders. Gut dysbiosis also leads to the development of colorectal cancer (CRC). Despite substantial research, little is known about the interactions between microorganisms, their hosts, and their environments, or whether dysbiosis is a cause or consequence of disease. According to a recent hypothesis, bacterial species living in the mucus layer of the colon may determine whether cellular homeostasis is retained or inflammatory processes are elicited, either through direct interaction with intestinal epithelium or indirectly via bacterial metabolites. Recently, high throughput deep-sequencing technology has enabled the characterization of the microbiota in patients suffering from intestinal or extra-intestinal disorders, and a strong association between dysbiosis and disease development was found. However, specific disease drivers still need to be identified in most cases. Small compounds and metabolites produced by gut bacterial flora act as signaling molecules, such as neurotransmitters and neuropeptides that can profoundly influence host physiology. These metabolites play a crucial role in modulating gut-brain crosstalk. There is growing evidence that neurological disorders such as Alzheimer's disease, Parkinson’s and others, may originate or be exaggerated in response to microbial dysbiosis either directly or indirectly interfering with the drugs through metabolites. The present evidence on the role of the gut microbiota in disease development and drug metabolism is summarized in this review. Based on available studies, we can explore the potential of gut flora to alleviate disease progression.

Immunomodulatory role of T helper cells in rheumatoid arthritis : a comprehensive research review.

Rheumatoid arthritis (RA) is an autoimmune disease that involves T and B cells and their reciprocal immune interactions with proinflammatory cytokines. T cells, an essential part of the immune system, play an important role in RA. T helper 1 (Th1) cells induce interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and interleukin (IL)-2, which are proinflammatory cytokines, leading to cartilage destruction and bone erosion. Th2 cells primarily secrete IL-4, IL-5, and IL-13, which exert anti-inflammatory and anti-osteoclastogenic effects in inflammatory arthritis models. IL-22 secreted by Th17 cells promotes the proliferation of synovial fibroblasts through induction of the chemokine C-C chemokine ligand 2 (CCL2). T follicular helper (Tfh) cells produce IL-21, which is key for B cell stimulation by the C-X-C chemokine receptor 5 (CXCR5) and coexpression with programmed cell death-1 (PD-1) and/or inducible T cell costimulator (ICOS). PD-1 inhibits T cell proliferation and cytokine production. In addition, there are many immunomodulatory agents that promote or inhibit the immunomodulatory role of T helper cells in RA to alleviate disease progression. These findings help to elucidate the aetiology and treatment of RA and point us toward the next steps.Cite this article: Bone Joint Res 2022;11(7):426–438.

The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air–liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.

Gastrin producing syngeneic mesenchymal stem cells protect non-obese diabetic mice from type 1 diabetes

Progressive destruction of pancreatic islet β-cells by immune cells is a primary feature of type 1 diabetes (T1D) and therapies that can restore the functional β-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide hormone that is produced by intestinal cells and foetal islets and can increase β-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a significant delay in hyperglycaemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycaemic mice caused the restoration of euglycemia for a considerable duration, and these therapeutic effects were associated with the protection of, and/or higher frequencies of, insulin-producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly upon treatment using Gastrin-MSCs or upon in vitro culture, pancreatic lymph node cells from Gastrin-MSC treated mice, upon ex vivo challenge with self-antigen, showed a Th2 and Th17 bias, and diminished the diabetogenic property in NOD-Rag1 deficient mice suggesting a disease protective immune modulation under Gastrin-MSC treatment associated protection from hyperglycaemia. Overall, this study shows the potential of production and delivery of Gastrin in vivo, by MSCs, in protecting insulin-producing β-cells and ameliorating the disease progression in T1D.

Probiotics for periodontal health-Current molecular findings.

Dysbiosis of the oral microbiome is associated with a variety of oral and systemic diseases, including periodontal disease. Oral dysbiosis in periodontal disease leads to an exacerbated host immune response that induces progressive periodontal tissue destruction and ultimately tooth loss. To counter the disease‐associated dysbiosis of the oral cavity, strategies have been proposed to reestablish a “healthy” microbiome via the use of probiotics. This study reviews the literature on the use of probiotics for modifying the oral microbial composition toward a beneficial state that might alleviate disease progression. Four in vitro and 10 preclinical studies were included in the analysis, and these studies explored the effects of probiotics on cultured biofilm growth and bacterial gene expressions, as well as modulation of the host response to inflammation. The current molecular findings on probiotics provide fundamental evidence for further clinical research for the use of probiotics in periodontal therapy. They also point out an important caveat: Changing the biofilm composition might alter the normal oral flora that is beneficial and/or critical for oral health.

Stimuli-responsive biomaterials for cardiac tissue engineering and dynamic mechanobiology.

Since the term “smart materials” was put forward in the 1980s, stimuli-responsive biomaterials have been used as powerful tools in tissue engineering, mechanobiology, and clinical applications. For the purpose of myocardial repair and regeneration, stimuli-responsive biomaterials are employed to fabricate hydrogels and nanoparticles for targeted delivery of therapeutic drugs and cells, which have been proved to alleviate disease progression and enhance tissue regeneration. By reproducing the sophisticated and dynamic microenvironment of the native heart, stimuli-responsive biomaterials have also been used to engineer dynamic culture systems to understand how cardiac cells and tissues respond to progressive changes in extracellular microenvironments, enabling the investigation of dynamic cell mechanobiology. Here, we provide an overview of stimuli-responsive biomaterials used in cardiovascular research applications, with a specific focus on cardiac tissue engineering and dynamic cell mechanobiology. We also discuss how these smart materials can be utilized to mimic the dynamic microenvironment during heart development, which might provide an opportunity to reveal the fundamental mechanisms of cardiomyogenesis and cardiac maturation.

Parallels between retinal and brain pathology and response to immunotherapy in old, late-stage Alzheimer's disease mouse models.

Despite growing evidence for the characteristic signs of Alzheimer's disease (AD) in the neurosensory retina, our understanding of retina–brain relationships, especially at advanced disease stages and in response to therapy, is lacking. In transgenic models of AD (APPSWE/PS1∆E9; ADtg mice), glatiramer acetate (GA) immunomodulation alleviates disease progression in pre‐ and early‐symptomatic disease stages. Here, we explored the link between retinal and cerebral AD‐related biomarkers, including response to GA immunization, in cohorts of old, late‐stage ADtg mice. This aged model is considered more clinically relevant to the age‐dependent disease. Levels of synaptotoxic amyloid β‐protein (Aβ)1–42, angiopathic Aβ1–40, non‐amyloidogenic Aβ1–38, and Aβ42/Aβ40 ratios tightly correlated between paired retinas derived from oculus sinister (OS) and oculus dexter (OD) eyes, and between left and right posterior brain hemispheres. We identified lateralization of Aβ burden, with one‐side dominance within paired retinal and brain tissues. Importantly, OS and OD retinal Aβ levels correlated with their cerebral counterparts, with stronger contralateral correlations and following GA immunization. Moreover, immunomodulation in old ADtg mice brought about reductions in cerebral vascular and parenchymal Aβ deposits, especially of large, dense‐core plaques, and alleviation of microgliosis and astrocytosis. Immunization further enhanced cerebral recruitment of peripheral myeloid cells and synaptic preservation. Mass spectrometry analysis identified new parallels in retino‐cerebral AD‐related pathology and response to GA immunization, including restoration of homeostatic glutamine synthetase expression. Overall, our results illustrate the viability of immunomodulation‐guided CNS repair in old AD model mice, while shedding light onto similar retino‐cerebral responses to intervention, providing incentives to explore retinal AD biomarkers.

Approved and Emerging Disease Modifying Therapies on Neurodegeneration in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune, chronic, progressive disease leading to a combination of inflammation, demyelination, and neurodegeneration throughout the central nervous system (CNS). The outcome of these processes can be visualized in magnetic resonance imaging (MRI) scans as brain atrophy, or brain volume loss (BVL), as well as lesions, “black holes” and spinal cord atrophy. MRI outcomes such as BVL have been used as biomarkers of neurodegeneration and other measures of MS disease progression in clinical research settings. Several FDA-approved medications seek to alleviate disease progression by reducing the impact of such factors as demyelination and neurodegeneration, but there are still many shortcomings that current clinical research aims to mitigate. This review attempts to provide an overview of the FDA-approved medications available for treating multiple sclerosis and their effect on neurodegeneration, measured by BVL.

Prefrontal functional connectivity analysis of cognitive decline for early diagnosis of mild cognitive impairment: a functional near-infrared spectroscopy study.

Cognitive decline (CD) is a major symptom of mild cognitive impairment (MCI). Patients with MCI have an increased likelihood of developing Alzheimer's disease (AD). Although a cure for AD is currently lacking, medication therapies and/or daily training in the early stage can alleviate disease progression and improve patients' quality of life. Accordingly, investigating CD-related biomarkers via brain imaging devices is crucial for early diagnosis. In particular, "portable" brain imaging devices enable frequent diagnostic checks as a routine clinical tool, and therefore increase the possibility of early AD diagnosis. This study aimed to comprehensively investigate functional connectivity (FC) in the prefrontal cortex measured by a portable functional near-infrared spectroscopy (fNIRS) device during a working memory (WM) task known as the delayed matching to sample (DMTS) task. Differences in prefrontal FC between healthy control (HC) (n = 23) and CD groups (n = 23) were examined. Intra-group analysis (one-sample t-test) revealed significantly greater prefrontal FC, especially left- and inter-hemispheric FC, in the CD group than in the HC. These observations could be due to a compensatory mechanism of the prefrontal cortex caused by hippocampal degeneration. Inter-group analysis (unpaired two-sample t-test) revealed significant intergroup differences in left- and inter-hemispheric FC. These attributes may serve as a novel biomarker for early detection of MCI. In addition, our findings imply that portable fNIRS devices covering the prefrontal cortex may be useful for early diagnosis of MCI.

Wang-Bi Capsule Alleviates the Joint Inflammation and Bone Destruction in Mice with Collagen-Induced Arthritis.

Wang-Bi Capsule (WB), a traditional Chinese medicine- (TCM-) based herbal formula, is currently used in clinic for the treatment of rheumatoid arthritis (RA) with positive clinical effects. However, its pharmacological mechanism of action in RA is still obscure. Therefore, this study established a collagen-induced arthritis (CIA) mice model to examine the efficacy of WB by using arthritis score, histological analysis, and micro-CT examination. Proinflammatory cytokines expression, osteoclast number, OPG/RANKL system, and NF-κB activation were then detected to further investigate the mechanism of WB in RA treatment. The results indicated that WB could alleviate the erythema and swelling of paws in CIA mice. It also inhibited the infiltration of inflammatory cells and bone destruction and increased bone density in joints of CIA mice. Mechanistic studies showed that WB treatment decreased the production of IL-1β, IL-6, and TNF-α in serum and joints of CIA mice. Moreover, it reduced the osteoclast number, increased OPG level, decreased RANKL level, and inhibited the activation of NF-κB in joints of CIA mice. In conclusion, this study demonstrated that WB could effectively alleviate disease progression of CIA mice by decreasing the IL-1β, IL-6, and TNF-α levels, modulating the OPG/RANKL system, and inhibiting the activation of NF-κB.

Risk factors associated with fatality of severe fever with thrombocytopenia syndrome: a meta-analysis.

Severe fever with thrombocytopenia syndrome is an emerging life-threatening infectious disease identified in 2009. Given high case-fatality rate among patients with severe fever with thrombocytopenia syndrome, identification of the risk factors at acute phase associated with fatality is crucial for treatment. Therefore, we aimed to meta-analytically evaluate risk factors of fatal clinical outcome of severe fever with thrombocytopenia syndrome. 238 fatal cases and 873 non-fatal cases from 12 studies were included in this meta-analysis. Elder age and high viral load were significantly associated with fatal clinical outcome. Further, severe fever with thrombocytopenia syndrome patients with fatal clinical outcome had significantly reduced level of albumin and platelet count, higher level of serum alanine aminotransferase, aspirate aminotransferase, lactic acid dehydrogenase and creatinine phosphokinase, and prolonged activated partial thromboplastin time, comparing with mild patients. These disturbed parameters function as predictors to warn fatal clinical outcome of the disease. Moreover, ribavirin has a minimal impact to alleviate disease progression of severe fever with thrombocytopenia syndrome. In conclusion, our finding demonstrates a panel of factors associated with fatality of SFTS disease, which have important implications during clinical practice.

Commentary: Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis.

Commentary: Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis.

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression. As a result, a vast body of research has focused on eliminating the mutant protein to broadly prevent downstream toxicity, either by silencing mutant protein expression or leveraging the endogenous protein quality control machinery. In the latter approach, a focus has been placed on four critical components of mutant protein degradation that are active in the nucleus, a key site of toxicity: disaggregation, ubiquitination, deubiquitination, and proteasomal activity. These machineries have unique functional components, but work together as a cellular defense system that can be successfully leveraged to alleviate disease phenotypes in several models of polyglutamine toxicity. This review will highlight recent advances in understanding both the potential and role of these components of the protein quality control machinery in polyglutamine disease pathophysiology.

Mesenchymal stem cells upregulate Treg cells via sHLA-G in SLE patients

BackgroundSoluble human leukocyte antigen-G (sHLA-G) is a non-classical HLA class I molecule, exhibiting strong immunosuppressive properties by inducing the differentiation of T regulatory cells (Treg). Mesenchymal stem cells (MSCs) transplantation alleviates disease progression in systemic lupus erythematosus (SLE) patients. However, the underlying mechanisms are largely unknown. ObjectivesTo explore whether sHLA-G is involved in upregulating effects of MSCs on Treg, which contributes to therapeutic effects of MSCs transplantation in SLE. MethodsThe serum sHLA-G levels of SLE patients and healthy controls were detected by ELISA. The percentages of peripheral blood CD4+ILT2+, CD8+ILT2+, CD19+ILT2+ cells and Treg cells were examined by flow cytometry. Ten patients with active SLE, refractory to conventional therapies, were infused with umbilical cord derived MSCs (UC-MSCs) and serum sHLA-G was measured 24h and 1month after infusion. The mice were divided into three groups: C57BL/6 mice, B6.MRL-Faslpr mice infused with phosphate buffer saline (PBS), and B6.MRL-Faslpr mice infused with bone marrow MSCs (BM-MSCs). Then, the concentrations of serum Qa-2 were detected. Peripheral blood mononuclear cells (PBMCs) were isolated from SLE patients and co-cultured with UC-MSCs for 3days at different ratios (50:1, 10:1, and 2:1) with or without HLA-G antibody, and the frequencies of CD4+CD25+Foxp3+ T cells were then determined by flow cytometry. ResultsThe concentrations of serum sHLA-G were comparable between SLE patients and healthy controls. However, there was a negative correlation between sHLA-G levels and SLE disease activity index (SLEDAI) scores in active SLE patients (SLEDAI>4). We found that serum sHLA-G levels were negatively correlated with blood urea nitrogen, serum creatinine and 24-hour urine protein in SLE patients. The sHLA-G levels were significantly lower in SLE patients with renal involvement than those without renal involvement. The expression of ILT2 on CD4+ T cells from SLE patients decreased significantly compared to that of healthy controls. A positive correlation between the frequencies of Treg and CD4+ILT2+ T cells was found in SLE patients. The levels of sHLA-G increased 24h post UC-MSCs transplantation. The concentrations of Qa-2 in BM-MSCs transplanted mice were significantly higher than those of control group. In vitro studies showed that MSCs increased the frequency of Treg cells in SLE patients in a dose-dependent manner, which was partly abrogated by the anti-HLA-G antibody. ConclusionsOur results suggested that MSCs may alleviate SLE through upregulating Treg cells, which was partly dependent on sHLA-G.

Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis

PurposeEmerging evidence has demonstrated that gut microbiome plays essential roles in the pathogenesis of human diseases in distal organs. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Treatment with the only drug approved by the US Food and Drug Administration for use in ALS, riluzole, extends a patient׳s life span by only a few months. Thus, there is an urgent need to develop novel interventions that for alleviate disease progression and improve quality of life in patients with ALS. Here we present evidence that intestinal dysfunction and dysbiosis may actively contribute to ALS pathophysiology. MethodsWe used G93A transgenic mice as a model of human ALS. The G93A mice show abnormal intestinal microbiome and damaged tight junctions before ALS disease onset. The mice were given 2% butyrate, a natural bacterial product, in the drinking water. ResultsIn mice fed with butyrate, intestinal microbial homeostasis was restored, gut integrity was improved, and life span was prolonged compared with those in control mice. At the cellular level, abnormal Paneth cells—specialized intestinal epithelial cells that regulate the host–bacterial interactions—were significantly decreased in the ALS mice treated with butyrate. In both ALS mice and intestinal epithelial cells cultured from humans, butyrate treatment was associated with decreased aggregation of the G93A superoxide dismutase 1 mutated protein. ImplicationsThe findings from this study highlight the complex role of the gut microbiome and intestinal epithelium in the progression of ALS and present butyrate as a potential therapeutic reagent for restoring ALS-related dysbiosis.

Pompe Disease and Autophagy: Partners in Crime, or Cause and Consequence?

Pompe disease or glycogen storage disease type II (OMIM: 232300) is a lysosomal storage disorder resulting from a partial or total lack of acid alphaglucosidase, which may produce muscle weakness, gait abnormalities, or even death by respiratory failure. In the last decade, autophagy has been proposed as a mechanism involved in the severity of symptoms related to this disorder and as a potential therapeutic target to alleviate disease progression. This review summarizes the relationship between autophagy and Pompe disease, including what information has been recently discovered and what remains unclear.

Characterization of NAD salvage pathways and their role in virulence in Streptococcus pneumoniae.

NAD is a necessary cofactor present in all living cells. Some bacteria cannot de novo synthesize NAD and must use the salvage pathway to import niacin or nicotinamide riboside via substrate importers NiaX and PnuC, respectively. Although homologues of these two importers and their substrates have been identified in other organisms, limited data exist in Streptococcus pneumoniae, specifically, on its effect on overall virulence. Here, we sought to characterize the substrate specificity of NiaX and PnuC in Str. pneumoniae TIGR4 and the contribution of these proteins to virulence of the pathogen. Although binding affinity of each importer for nicotinamide mononucleotide may overlap, we found NiaX to specifically import nicotinamide and nicotinic acid, and PnuC to be primarily responsible for nicotinamide riboside import. Furthermore, a pnuC mutant is completely attenuated during both intranasal and intratracheal infections in mice. Taken together, these findings underscore the importance of substrate salvage in pneumococcal pathogenesis and indicate that PnuC could potentially be a viable small-molecule therapeutic target to alleviate disease progression in the host.

Low-density oligonucleotide microarrays - A major step in Wilson's disease diagnosis.

Low-density oligonucleotide microarrays - A major step in Wilson's disease diagnosis.

A novel acylaminoimidazole derivative, WN1316, alleviates disease progression via suppression of glial inflammation in ALS mouse model.

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron degenerative disease. Given that oxidative stress and resulting chronic neuronal inflammation are thought to be central pathogenic, anti-oxidative agents and modulators of neuronal inflammation could be potential therapies for ALS. We report here that the novel small molecular compound, 2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316) selectively suppresses oxidative stress-induced cell death and neuronal inflammation in the late-stage ALS mice. WN1316 has high blood-brain-barrier permeability and water solubility, and boosts both neuronal apoptosis inhibitory protein (NAIP) and NF-E2-related factor 2 (Nrf2) which governed glutathione (GSH)-related anti-oxidation pathway protecting motor neurons against oxidative injuries. Post-onset oral administration of low dose (1–100 µg/kg/day) WN1316 in ALS(SOD1H46R) and ALS(SOD1G93A) mice resulted in sustained improved motor function and post onset survival rate. Immunohistochemical analysis revealed less DNA oxidative damage and motor neuronal inflammation as well as repression of both microgliosis and astrocytosis, concomitant down regulation of interleukin-1β and inducible nitric oxide synthase, and preservation of the motoneurons in anterior horn of lumbar spinal cord and skeletal muscle (quadriceps femoris). Thus, WN1316 would be a novel therapeutic agent for ALS.